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1. Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment

Author

Georghiou, Sophia B, Rodwell, Timothy C, Korobitsyn, Alexei, Abbadi, Said H, Ajbani, Kanchan, Alffenaar, Jan-Willem, Alland, David, Alvarez, Nataly, Andres, Sönke, Ardizzoni, Elisa, Aubry, Alexandra, Baldan, Rossella, Ballif, Marie, Barilar, Ivan, Böttger, Erik C, Chakravorty, Soumitesh, Claxton, Pauline M, Cirillo, Daniela M, Comas, Iñaki, Coulter, Chris, Denkinger, Claudia M, Derendinger, Brigitta, Desmond, Edward P, de Steenwinkel, Jurriaan EM, Dheda, Keertan, Diacon, Andreas H, Dolinger, David L, Dooley, Kelly E, Egger, Matthias, Ehsani, Soudeh, Farhat, Maha R, Fattorini, Lanfranco, Finci, Iris, Le Ray, Laure Fournier, Furió, Victoria, Groenheit, Ramona, Gumbo, Tawanda, Heysell, Scott K, Hillemann, Doris, Hoffmann, Harald, Hsueh, Po-Ren, Hu, Yi, Huang, Hairong, Hussain, Alamdar, Ismail, Farzana, Izumi, Kiyohiko, Jagielski, Tomasz, Johnson, John L, Kambli, Priti, Kaniga, Koné, Karunaratne, GHR Eranga, Sharma, Meenu Kaushal, Keller, Peter M, Kelly, Ellis C, Kholina, Margarita, Kohli, Mikashmi, Kranzer, Katharina, Laurenson, Ian F, Limberis, Jason, Lin, S-Y Grace, Liu, Yongge, López-Gavín, Alexandre, Lyander, Anna, Machado, Diana, Martinez, Elena, Masood, Faisal, Mitarai, Satoshi, Mvelase, Nomonde R, Niemann, Stefan, Nikolayevskyy, Vladyslav, Maurer, Florian P, Merker, Matthias, Miotto, Paolo, Omar, Shaheed V, Otto-Knapp, Ralf, Palaci, Moisés, Gutiérrez, Juan José Palacios, Peacock, Sharon J, Peloquin, Charles A, Perera, Jennifer, Pierre-Audigier, Catherine, Pholwat, Suporn, Posey, James E, Prammananan, Therdsak, Rigouts, Leen, Robledo, Jaime, Rockwood, Neesha, Rodrigues, Camilla, Salfinger, Max, Schechter, Marcos C, Seifert, Marva, Sengstake, Sarah, Shinnick, Thomas, Shubladze, Natalia, Sintchenko, Vitali, Sirgel, Frederick, Somasundaram, Sulochana, Sterling, Timothy R, Spitaleri, Andrea, and Streicher, Elizabeth

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Biodefense, Antimicrobial Resistance, Prevention, Rare Diseases, Emerging Infectious Diseases, Tuberculosis, Clinical Research, Vaccine Related, Orphan Drug, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Good Health and Well Being, Antitubercular Agents, Drug Resistance, Bacterial, Drug Resistance, Multiple, Bacterial, Humans, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Tuberculosis, Multidrug-Resistant, Antimycobacterial Susceptibility Testing Group, Medical and Health Sciences, Respiratory System, Cardiovascular medicine and haematology
Abstract

Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance. https://bit.ly/3i43wb6

Published
2022

4. Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study

Author

Dheda, Keertan, Limberis, Jason D, Pietersen, Elize, Phelan, Jody, Esmail, Aliasgar, Lesosky, Maia, Fennelly, Kevin P, te Riele, Julian, Mastrapa, Barbara, Streicher, Elizabeth M, Dolby, Tania, Abdallah, Abdallah M, Ben-Rached, Fathia, Simpson, John, Smith, Liezel, Gumbo, Tawanda, van Helden, Paul, Sirgel, Frederick A, McNerney, Ruth, Theron, Grant, Pain, Arnab, Clark, Taane G, and Warren, Robin M

Published
2017
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6. Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment

Author

Ministerio de Ciencia e Innovación (España), European Research Council, Comas, Iñaki [0000-0001-5504-9408], Antimycobacterial Susceptibility Testing Group, Georghiou, Sophia B., Rodwell, Timothy C., Korobitsyn, Alexei, Abbadi, Said H., Ajbani, Kanchan, Alffenaar, Jan-Willem, Alland, David, Alvarez, Nataly, Andres, Sönke, Ardizzoni, Elisa, Aubry, Alexandra, Baldan, Rossella, Ballif, Marie, Barilar, Ivan, Böttger, Erik C., Chakravorty, Soumitesh, Claxton, Pauline M., Cirillo, Daniela M., Comas, Iñaki, Coulter, Chris, Denkinger, Claudia M., Derendinger, Brigitta, Desmond, Edward P., Steenwinkel, Jurriaan E. M. de, Dheda, Keertan, Diacon, Andreas H., Dolinger, David L., Dooley, Kelly E., Egger, Matthias, Ehsani, Soudeh, Farhat, Maha R., Fattorini, Lanfranco, Finci, Iris, Fournier Le Ray, Laure, Furió, Victoria, Groenheit, Ramona, Gumbo, Tawanda, Heysell, Scott K., Hillemann, Doris, Hoffmann, Harald, Hsueh, Po-Ren, Hu, Yi, Huang, Hairong, Hussain, Alamdar, Ismail, Farzana, Izumi, Kiyohiko, Jagielski, Tomasz, Johnson, John L., Kambli, Priti, Kaniga, Koné, Karunaratne, G. H. R. Eranga, Sharma, Meenu Kaushal, Keller, Peter M., Kelly, Ellis C., Kholina, Margarita, Kohli, Mikashmi, Kranzer, Katharina, Laurenson, Ian F., Limberis, Jason, Lin, S-Y. Grace, Liu, Yongge, López-Gavín, Alexandre, Lyander, Anna, Machado, Diana, Martínez, Elena, Masood, Faisal, Mitarai, Satoshi, Mvelase, Nomonde R., Niemann, Stefan, Nikolayevskyy, Vladyslav, Maurer, Florian P., Merker, Matthias, Miotto, Paolo, Omar, Shaheed V., Otto-Knapp, Ralf, Palaci, Moisés, Palacios Gutiérrez, Juan José, Peacock, Sharon J., Peloquin, Charles A., Perera, Jennifer, Pierre-Audigier, Catherine, Pholwat, Suporn, Posey, James E., Prammananan, Therdsak, Rigouts, Leen, Robledo, Jaime, Rockwood, Neesha, Rodrigues, Camilla, Salfinger, Max, Schechter, Marcos C., Seifert, Marva, Sengstake, Sarah, Shinnick, Thomas, Shubladze, Natalia, Sintchenko, Vitali, Sirgel, Frederick, Somasundaram, Sulochana, Sterling, Timothy R., Spitaleri, Andrea, Streicher, Elizabeth, Supply, Philip, Svensson, Erik, Tagliani, Elisa, Tahseen, Sabira, Takaki, Akiko, Theron, Grant, Torrea, Gabriela, Van Deun, Armand, van Ingen, Jakko, Van Rie, Annelies, van Soolingen, Dick, Vargas Jr, Roger, Venter, Amour, Veziris, Nicolas, Villellas, Cristina, Viveiros, Miguel, Warren, Robin, Wen, Shu'an, Werngren, Jim, Wilkinson, Robert J., Yang, Caie, Yılmaz, F. Ferda, Zhang, Tingting, Zimenkov, Danila, Ismail, Nazir, Köser, Claudio U., Schön, Thomas, Ministerio de Ciencia e Innovación (España), European Research Council, Comas, Iñaki [0000-0001-5504-9408], Antimycobacterial Susceptibility Testing Group, Georghiou, Sophia B., Rodwell, Timothy C., Korobitsyn, Alexei, Abbadi, Said H., Ajbani, Kanchan, Alffenaar, Jan-Willem, Alland, David, Alvarez, Nataly, Andres, Sönke, Ardizzoni, Elisa, Aubry, Alexandra, Baldan, Rossella, Ballif, Marie, Barilar, Ivan, Böttger, Erik C., Chakravorty, Soumitesh, Claxton, Pauline M., Cirillo, Daniela M., Comas, Iñaki, Coulter, Chris, Denkinger, Claudia M., Derendinger, Brigitta, Desmond, Edward P., Steenwinkel, Jurriaan E. M. de, Dheda, Keertan, Diacon, Andreas H., Dolinger, David L., Dooley, Kelly E., Egger, Matthias, Ehsani, Soudeh, Farhat, Maha R., Fattorini, Lanfranco, Finci, Iris, Fournier Le Ray, Laure, Furió, Victoria, Groenheit, Ramona, Gumbo, Tawanda, Heysell, Scott K., Hillemann, Doris, Hoffmann, Harald, Hsueh, Po-Ren, Hu, Yi, Huang, Hairong, Hussain, Alamdar, Ismail, Farzana, Izumi, Kiyohiko, Jagielski, Tomasz, Johnson, John L., Kambli, Priti, Kaniga, Koné, Karunaratne, G. H. R. Eranga, Sharma, Meenu Kaushal, Keller, Peter M., Kelly, Ellis C., Kholina, Margarita, Kohli, Mikashmi, Kranzer, Katharina, Laurenson, Ian F., Limberis, Jason, Lin, S-Y. Grace, Liu, Yongge, López-Gavín, Alexandre, Lyander, Anna, Machado, Diana, Martínez, Elena, Masood, Faisal, Mitarai, Satoshi, Mvelase, Nomonde R., Niemann, Stefan, Nikolayevskyy, Vladyslav, Maurer, Florian P., Merker, Matthias, Miotto, Paolo, Omar, Shaheed V., Otto-Knapp, Ralf, Palaci, Moisés, Palacios Gutiérrez, Juan José, Peacock, Sharon J., Peloquin, Charles A., Perera, Jennifer, Pierre-Audigier, Catherine, Pholwat, Suporn, Posey, James E., Prammananan, Therdsak, Rigouts, Leen, Robledo, Jaime, Rockwood, Neesha, Rodrigues, Camilla, Salfinger, Max, Schechter, Marcos C., Seifert, Marva, Sengstake, Sarah, Shinnick, Thomas, Shubladze, Natalia, Sintchenko, Vitali, Sirgel, Frederick, Somasundaram, Sulochana, Sterling, Timothy R., Spitaleri, Andrea, Streicher, Elizabeth, Supply, Philip, Svensson, Erik, Tagliani, Elisa, Tahseen, Sabira, Takaki, Akiko, Theron, Grant, Torrea, Gabriela, Van Deun, Armand, van Ingen, Jakko, Van Rie, Annelies, van Soolingen, Dick, Vargas Jr, Roger, Venter, Amour, Veziris, Nicolas, Villellas, Cristina, Viveiros, Miguel, Warren, Robin, Wen, Shu'an, Werngren, Jim, Wilkinson, Robert J., Yang, Caie, Yılmaz, F. Ferda, Zhang, Tingting, Zimenkov, Danila, Ismail, Nazir, Köser, Claudio U., and Schön, Thomas

Abstract

Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance.

Published
2022

7. Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid

Author

Bateson, Anna, primary, Ortiz Canseco, Julio, additional, McHugh, Timothy D., additional, Witney, Adam A., additional, Feuerriegel, Silke, additional, Merker, Matthias, additional, Kohl, Thomas A., additional, Utpatel, Christian, additional, Niemann, Stefan, additional, Andres, Sönke, additional, Kranzer, Katharina, additional, Maurer, Florian P, additional, Ghodousi, Arash, additional, Borroni, Emanuele, additional, Cirillo, Daniela Maria, additional, Wijkander, Maria, additional, Toro, Juan C., additional, Groenheit, Ramona, additional, Werngren, Jim, additional, Machado, Diana, additional, Viveiros, Miguel, additional, Warren, Robin M., additional, Sirgel, Frederick, additional, Dippenaar, Anzaan, additional, Köser, Claudio U., additional, Sun, Eugene, additional, and Timm, Juliano, additional

Published
2022
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8. Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment

Author

Antimycobacterial Susceptibility Testing Group, Georghiou, Sophia B., Rodwell, Timothy C., Korobitsyn, Alexei, Abbadi, Said H., Ajbani, Kanchan, Alffenaar, Jan-Willem, Alland, David, Alvarez, Nataly, Andres, Sönke, Ardizzoni, Elisa, Aubry, Alexandra, Baldan, Rossella, Ballif, Marie, Barilar, Ivan, Böttger, Erik C., Chakravorty, Soumitesh, Claxton, Pauline M., Cirillo, Daniela M., Comas, Iñaki, Coulter, Chris, Denkinger, Claudia M., Derendinger, Brigitta, Desmond, Edward P., Steenwinkel, Jurriaan E. M. de, Dheda, Keertan, Diacon, Andreas H., Dolinger, David L., Dooley, Kelly E., Egger, Matthias, Ehsani, Soudeh, Farhat, Maha R., Fattorini, Lanfranco, Finci, Iris, Fournier Le Ray, Laure, Furió, Victoria, Groenheit, Ramona, Gumbo, Tawanda, Heysell, Scott K., Hillemann, Doris, Hoffmann, Harald, Hsueh, Po-Ren, Hu, Yi, Huang, Hairong, Hussain, Alamdar, Ismail, Farzana, Izumi, Kiyohiko, Jagielski, Tomasz, Johnson, John L., Kambli, Priti, Kaniga, Koné, Karunaratne, G. H. R. Eranga, Sharma, Meenu Kaushal, Keller, Peter M., Kelly, Ellis C., Kholina, Margarita, Kohli, Mikashmi, Kranzer, Katharina, Laurenson, Ian F., Limberis, Jason, Lin, S-Y. Grace, Liu, Yongge, López-Gavín, Alexandre, Lyander, Anna, Machado, Diana, Martínez, Elena, Masood, Faisal, Mitarai, Satoshi, Mvelase, Nomonde R., Niemann, Stefan, Nikolayevskyy, Vladyslav, Maurer, Florian P., Merker, Matthias, Miotto, Paolo, Omar, Shaheed V., Otto-Knapp, Ralf, Palaci, Moisés, Palacios Gutiérrez, Juan José, Peacock, Sharon J., Peloquin, Charles A., Perera, Jennifer, Pierre-Audigier, Catherine, Pholwat, Suporn, Posey, James E., Prammananan, Therdsak, Rigouts, Leen, Robledo, Jaime, Rockwood, Neesha, Rodrigues, Camilla, Salfinger, Max, Schechter, Marcos C., Seifert, Marva, Sengstake, Sarah, Shinnick, Thomas, Shubladze, Natalia, Sintchenko, Vitali, Sirgel, Frederick, Somasundaram, Sulochana, Sterling, Timothy R., Spitaleri, Andrea, Streicher, Elizabeth, Supply, Philip, Svensson, Erik, Tagliani, Elisa, Tahseen, Sabira, Takaki, Akiko, Theron, Grant, Torrea, Gabriela, Van Deun, Armand, van Ingen, Jakko, Van Rie, Annelies, van Soolingen, Dick, Vargas Jr, Roger, Venter, Amour, Veziris, Nicolas, Villellas, Cristina, Viveiros, Miguel, Warren, Robin, Wen, Shu'an, Werngren, Jim, Wilkinson, Robert J., Yang, Caie, Yılmaz, F. Ferda, Zhang, Tingting, Zimenkov, Danila, Ismail, Nazir, Köser, Claudio U., Schön, Thomas, University of Zurich, Antimycobacterial Susceptibility Testing Group, Department of Genetics [Cambridge], University of Cambridge [UK] (CAM), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Médical de l'Institut Pasteur (CMIP), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut de médecine et d'épidémiologie appliquée [AP-HP Hôpital Bichat-Claude Bernard] (IMEA), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), As current or former employees or consultants for FIND, the work of R.B. Baldan, I. Comas, C.M. Denkinger, D.L. Dolinger, S.B. Georghiou, C.U. Köser and T.C. Rodwell on the systematic reviews, including this viewpoint, was supported by Unitaid (grant 2019-32-FIND MDR), BMGF (grant OPP1105925), the German Federal Ministry of Education and Research through KfW, the Dutch Ministry of Foreign Affairs, the Australian Department of Foreign Affairs and Trade, and UK aid from the British people. N. Alvarez and J. Robledo are funded by MinCiencias, Colombia (number 221389666216 CT-783-2018). A. Aubry and N. Veziris work at the Centre National de Reference des Mycobactéries, which receives an annual grant from Santé Publique France and have received research grants from Janssen for studies on bedaquiline. P. Claxton and I.F. Laurenson are funded through National Services Scotland. I. Comas was supported by PID2019-104477RB-I00 from the Spanish Science Ministry and by ERC (CoG 101001038). M. Egger is supported by the Swiss National Science Foundation (grant number 320030_153442 and 189498) and the US National Institutes of Health, National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, the National Institute of Mental Health, the National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Diabetes and Digestive and Kidney Diseases, the Fogarty International Center, and the National Library of Medicine: Asia-Pacific, U01AI069907, CCASAnet, U01AI069923, Central Africa, U01AI096299, East Africa, U01AI069911, NA-ACCORD, U01AI069918, Southern Africa, U01AI069924, West Africa, U01AI069919. M.R. Farhat is supported by NIH NIAID R01AI155765. S.K. Heysell was funded by NIH NIAID grants R01 AI137080 and U01 AI150508. T. Jagielski was supported by a DAINA grant (number 2017/27/L/NZ6/03279) from the National Science Centre, Poland. J.L. Johnson was supported by contracts NO1-AI95383 and NO1-AI-70022 of the US National Institutes of Health. P.M. Keller was supported by Innosuisse 36198.1 IP-LS. C.U. Köser is a research associate at Wolfson College and visiting scientist at the Department of Genetics, University of Cambridge. The Federal Government of Germany supported C.U. Köser as part of his work for the European Laboratory Initiative, WHO Regional Office for Europe. C.U. Köser was further supported by the Royal Society of Tropical Medicine and Hygiene and the National Institute for Health Research Cambridge Biomedical Research Centre and received an observership by the European Society of Clinical Microbiology and Infectious Diseases to the EUCAST Development Laboratory for Bacteria (Växjö, Sweden), hosted by Gunnar Kahlmeter and Erika Matuschek. D. Machado and M. Viveiros are funded in part by Fundação para a Ciência e a Tecnologia, Portugal (PTDC/BIA-MIC/30692/2017, UID/Multi/04413/2020 and DL57/ CEECIND/0256/2017). S. Niemann is supported by the German Center for Infection Research, Excellenz Cluster Precision Medicine in Chronic Inflammation EXC 2167, Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG). S.V. Omar has received funding to prepare and provide training for Janssen Pharmaceutica activities. L. Rigouts is supported by the Belgian Directorate General for Development. T.C. Rodwell was additionally funded in part by FIND and NIH NIAD, grants: P30 AI036214 and R21 AI135756. T. Schön is funded by the Swedish Heart and Lung Foundation and the Swedish Research Council. T.R. Sterling has received funding from the US National Institutes of Health and the Centers for Disease Control and Prevention. G. Theron and R. Warren are supported by baseline funding from the South African Medical Research Council. R.J. Wilkinson receives funding from the Wellcome Trust (203135) and from the Francis Crick Institute, which is supported by Cancer Research UK (FC0010218), UKRI (FC0010218) and the Wellcome Trust (FC0010218), Ministerio de Ciencia e Innovación (España), European Research Council, Comas, Iñaki, Comas, Iñaki [0000-0001-5504-9408], Antimycobacterial Susceptibility T, and Wellcome Trust

Subjects
[SDV]Life Sciences [q-bio], Respiratory System, Drug Resistance, Antitubercular Agents, Infektionsmedicin, Medical and Health Sciences, Drug Resistance, Multiple, Bacterial, Tuberculosis, Multidrug-Resistant, 11 Medical and Health Sciences, Human Biology & Physiology, MESH: Microbial Sensitivity Tests, 10179 Institute of Medical Microbiology, Bacterial, Multidrug-Resistant, Infectious Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Life Sciences & Biomedicine, Multiple, Model organisms, Pulmonary and Respiratory Medicine, Infectious Medicine, Immunology, Infectious Disease, 610 Medicine & health, Microbial Sensitivity Tests, Vaccine Related, Rare Diseases, Clinical Research, Biodefense, MESH: Drug Resistance, Bacterial, Drug Resistance, Bacterial, Tuberculosis, Humans, Science & Technology, MESH: Humans, Antimycobacterial Susceptibility Testing Group, FOS: Clinical medicine, Prevention, MESH: Drug Resistance, Multiple, Bacterial, Mycobacterium tuberculosis, Eucast, MESH: Antitubercular Agents, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Orphan Drug, Emerging Infectious Diseases, Good Health and Well Being, 2740 Pulmonary and Respiratory Medicine, 570 Life sciences, biology, Human medicine, Antimicrobial Resistance, Model
Abstract

11 páginas, 2 figuras, 1 tabla, Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance., I. Comas was supported by PID2019-104477RB-I00 from the Spanish Science Ministry and by ERC (CoG 101001038)

Published
2022

9. 1,3-Diarylpyrazolyl-acylsulfonamides as Potent Anti-tuberculosis Agents Targeting Cell Wall Biosynthesis in Mycobacterium tuberculosis

Author

Khonde, Lutete Peguy, Müller, Rudolf, Boyle, Grant A., Reddy, Virsinha, Nchinda, Aloysius T., Eyermann, Charles J., Fienberg, Stephen, Singh, Vinayak, Myrick, Alissa, Abay, Efrem, Njoroge, Mathew, Lawrence, Nina, Su, Qin, Myers, Timothy G., Boshoff, Helena I. M., Barry, Clifton E., Sirgel, Frederick A., van Helden, Paul D., Massoudi, Lisa M., Robertson, Gregory T., Lenaerts, Anne J., Basarab, Gregory S., Ghorpade, Sandeep R., and Chibale, Kelly

Abstract

This is the accepted manuscript version of the work published in its final form as Khonde, Lutete Peguy;Müller, Rudolf;Boyle, Grant A.;Reddy, Virsinha;Nchinda, Aloysius T.;Eyermann, Charles J.;Fienberg, Stephen;Singh, Vinayak;Myrick, Alissa;Abay, Efrem;Njoroge, Mathew;Lawrence, Nina;Su, Qin;Myers, Timothy G.;Boshoff, Helena I. M.;Barry, Clifton E.;Sirgel, Frederick A.;van Helden, Paul D.;Massoudi, Lisa M.;Robertson, Gregory T.;Lenaerts, Anne J.;Basarab, Gregory S.;Ghorpade, Sandeep R.;Chibale, Kelly. Journal of Medicinal Chemistry Volume: 64 issue: 17, page(s): 12790–12807.https://doi.org/10.1021/acs.jmedchem.1c00837 Deposited byshareyourpaper.organdopenaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailinghelp@openaccessbutton.org.

Published
2021
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11. Rifampicin-Monoresistant Tuberculosis Is Not the Same as Multidrug-Resistant Tuberculosis: a Descriptive Study from Khayelitsha, South Africa

Author

Salaam-Dreyer, Zubeida, primary, Streicher, Elizabeth M., additional, Sirgel, Frederick A., additional, Menardo, Fabrizio, additional, Borrell, Sonia, additional, Reinhard, Miriam, additional, Doetsch, Anna, additional, Cudahy, Patrick G. T., additional, Mohr-Holland, Erika, additional, Daniels, Johnny, additional, Dippenaar, Anzaan, additional, Nicol, Mark P., additional, Gagneux, Sebastien, additional, Warren, Robin M., additional, and Cox, Helen, additional

Published
2021
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12. Emergence and spread of extensively and totally drug-resistant tuberculosis, South Africa

Author

Klopper, Marisa, Warren, Robin Mark, Hayes, Cindy, van Pittius, Nicolaas Claudius Gey, Streicher, Elizabeth Maria, Muller, Borna, Sirgel, Frederick Adriaan, Chabula-Nxiweni, Mamisa, Hoosain, Ebrahim, Coetzee, Gerrit, van Helden, Paul David, Victor, Thomas Calldo, and Trollip, Andre Phillip

Subjects
Drug resistance in microorganisms -- Research, Tuberculosis -- Risk factors -- Research -- Drug therapy, Disease transmission -- Research, Health
Abstract

The emergence of drug-resistant tuberculosis (TB) is of major concern to TB control in South Africa. A countrywide survey in 2002 revealed that 1.8% of all new TB patients and [...]

Published
2013
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13. 1,3-Diarylpyrazolyl-acylsulfonamides as Potent Anti-tuberculosis Agents Targeting Cell Wall Biosynthesis in Mycobacterium tuberculosis

Author

Khonde, Lutete Peguy, primary, Müller, Rudolf, additional, Boyle, Grant A., additional, Reddy, Virsinha, additional, Nchinda, Aloysius T., additional, Eyermann, Charles J., additional, Fienberg, Stephen, additional, Singh, Vinayak, additional, Myrick, Alissa, additional, Abay, Efrem, additional, Njoroge, Mathew, additional, Lawrence, Nina, additional, Su, Qin, additional, Myers, Timothy G., additional, Boshoff, Helena I. M., additional, Barry, Clifton E., additional, Sirgel, Frederick A., additional, van Helden, Paul D., additional, Massoudi, Lisa M., additional, Robertson, Gregory T., additional, Lenaerts, Anne J., additional, Basarab, Gregory S., additional, Ghorpade, Sandeep R., additional, and Chibale, Kelly, additional

Published
2021
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14. Rifampicin mono-resistant tuberculosis is not the same as multidrug-resistant tuberculosis: a descriptive study from Khayelitsha, South Africa

Author

Salaam-Dreyer, Zubeida, primary, Streicher, Elizabeth M., additional, Sirgel, Frederick A., additional, Menardo, Fabrizio, additional, Borrell, Sonia, additional, Reinhard, Miriam, additional, Doetsch, Anna, additional, Cudahy, Patrick G.T., additional, Mohr-Holland, Erika, additional, Daniels, Johnny, additional, Dippenaar, Anzaan, additional, Nicol, Mark P., additional, Gagneux, Sebastien, additional, Warren, Robin M., additional, and Cox, Helen, additional

Published
2021
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16. Antitubercular 2-Pyrazolylpyrimidinones: Structure–Activity Relationship and Mode-of-Action Studies

Author

Soares de Melo, Candice, primary, Singh, Vinayak, additional, Myrick, Alissa, additional, Simelane, Sandile B., additional, Taylor, Dale, additional, Brunschwig, Christel, additional, Lawrence, Nina, additional, Schnappinger, Dirk, additional, Engelhart, Curtis A., additional, Kumar, Anuradha, additional, Parish, Tanya, additional, Su, Qin, additional, Myers, Timothy G., additional, Boshoff, Helena I. M., additional, Barry, Clifton E., additional, Sirgel, Frederick A., additional, van Helden, Paul D., additional, Buchanan, Kirsteen I., additional, Bayliss, Tracy, additional, Green, Simon R., additional, Ray, Peter C., additional, Wyatt, Paul G., additional, Basarab, Gregory S., additional, Eyermann, Charles J., additional, Chibale, Kelly, additional, and Ghorpade, Sandeep R., additional

Published
2021
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17. High frequency of bedaquiline resistance in programmatically treated drug-resistant TB patients with sustained culture-positivity in Cape Town, South Africa

Author

Derendinger, Brigitta, additional, Dippenaar, Anzaan, additional, de Vos, Margaretha, additional, Alberts, Rudi, additional, Sirgel, Frederick, additional, Dolby, Tania, additional, Spies, Claudia, additional, Rigouts, Leen, additional, Metcalfe, John, additional, Engelthaler, David, additional, Warren, Rob, additional, Cox, Helen, additional, and Theron, Grant, additional

Published
2021
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21. Minority Mycobacterium tuberculosis Genotypic Populations as an Indicator of Subsequent Phenotypic Resistance

Author

Engelthaler, David M., primary, Streicher, Elizabeth M., additional, Kelley, Erin J., additional, Allender, Christopher J., additional, Wiggins, Kristin, additional, Jimenez, Dulce, additional, Lemmer, Darrin, additional, Vittinghoff, Eric, additional, Theron, Grant, additional, Sirgel, Frederick A., additional, Warren, Robin M., additional, and Metcalfe, John Z., additional

Published
2019
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22. Novel Antitubercular 6-Dialkylaminopyrimidine Carboxamides from Phenotypic Whole-Cell High Throughput Screening of a SoftFocus Library: Structure–Activity Relationship and Target Identification Studies

Author

Wilson, Colin R, Gessner, Richard K, Moosa, Atica, Seldon, Ronnett, Warner, Digby F, Mizrahi, Valerie, Soares de Melo, Candice, Simelane, Sandile B, Nchinda, Aloysius, Abay, Efrem, Taylor, Dale, Njoroge, Mathew, Brunschwig, Christel, Lawrence, Nina, Boshoff, Helena I M, Barry, Clifton E, Sirgel, Frederick A, van Helden, Paul, Harris, C John, Gordon, Richard, Ghidelli-Disse, Sonja, Pflaumer, Hannah, Boesche, Markus, Drewes, Gerard, Sanz, Olalla, Santos, Gracia, Rebollo-Lopez, Maria José, Urones, Beatriz, Selenski, Carolyn, Lafuente-Monasterio, Maria Jose, Axtman, Matthew, Lelièvre, Joël, Ballell, Lluis, Mueller, Rudolf, Street, Leslie J, Ghorpade, Sandeep R, and Chibale, Kelly

Subjects
Male, Proteomics, Antitubercular Agents, Administration, Oral, Blood Proteins, Mycobacterium tuberculosis, Article, High-Throughput Screening Assays, Mice, Inbred C57BL, Small Molecule Libraries, Structure-Activity Relationship, Pyrimidines, Drug Stability, Microsomes, Liver, Animals, Humans
Abstract

A BioFocus DPI SoftFocus library of ∼35 000 compounds was screened against Mycobacterium tuberculosis (Mtb) in order to identify novel hits with antitubercular activity. The hits were evaluated in biology triage assays to exclude compounds suggested to function via frequently encountered promiscuous mechanisms of action including inhibition of the QcrB subunit of the cytochrome bc1 complex, disruption of cell-wall homeostasis, and DNA damage. Among the hits that passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series was prioritized for hit to lead optimization. Compounds from this series were active against clinical Mtb strains, while no cross-resistance to conventional antituberculosis drugs was observed. This suggested a novel mechanism of action, which was confirmed by chemoproteomic analysis leading to the identification of BCG_3193 and BCG_3827 as putative targets of the series with unknown function. Initial structure-activity relationship studies have resulted in compounds with moderate to potent antitubercular activity and improved physicochemical properties.

Published
2017

24. Linezolid Pharmacokinetics in South African Patients with Drug-Resistant Tuberculosis and a High Prevalence of HIV Coinfection

Author

Wasserman, Sean, primary, Denti, Paolo, additional, Brust, James C. M., additional, Abdelwahab, Mahmoud, additional, Hlungulu, Siphokazi, additional, Wiesner, Lubbe, additional, Norman, Jennifer, additional, Sirgel, Frederick A., additional, Warren, Robin M., additional, Esmail, Aliasgar, additional, Dheda, Keertan, additional, Gandhi, Neel R., additional, Meintjes, Graeme, additional, and Maartens, Gary, additional

Published
2019
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27. Discordances between molecular assays for rifampicin resistance in Mycobacterium tuberculosis: frequency, mechanisms and clinical impact.

Author

Rie, Annelies Van, Whitfield, Michael G, Vos, Elise De, Scott, Lesley, Silva, Pedro Da, Hayes, Cindy, Heupink, Tim H, Sirgel, Frederick A, Stevens, Wendy, Warren, Robin M, Van Rie, Annelies, De Vos, Elise, and Da Silva, Pedro

Subjects
RESEARCH, RESEARCH methodology, MEDICAL cooperation, EVALUATION research, COMPARATIVE studies, PSYCHOLOGICAL tests, MYCOBACTERIUM tuberculosis, IMPACT of Event Scale, RESEARCH funding, RIFAMPIN, DRUG resistance in microorganisms, FAMILY relations, ANTIBIOTICS, PHARMACODYNAMICS
Abstract

Background: Molecular assays are endorsed for detection and confirmation of rifampicin-resistant TB. The frequency, causal mechanisms and impact of discordant results between molecular tests are not well understood.Methods: The prevalence of discordant results was determined by pairwise comparison of molecular test results in a cohort of 749 rifampicin-resistant TB patients in three South African provinces. Culture isolates were sent to a research laboratory for WGS and rifampicin MIC determination. Clinical information was collected through medical file review.Results: The prevalence of discordances between Xpert MTB/RIF and MTBDRplus was 14.5% (95% CI 10.9%-18.9%), 5.6% (95% CI 2.2%-13.4%) between two consecutive Xpert assays and 4.2% (95% CI 2.2%-7.8%) between two consecutive MTBDRplus assays. Likely mechanisms of discordances were false rifampicin susceptibility on MTBDRplus (due to variants not included in mutant probes or heteroresistance with loss of minor variants in culture), false resistance on molecular assay in rifampicin-susceptible isolates, and human error. The healthcare worker changed the treatment regimen in 33% of patients with discordant results and requested 232 additional molecular tests after a first confirmatory test was performed in 460 patients. A follow-up Xpert assay would give the healthcare worker the 'true' rifampicin-resistant TB diagnosis in at least 73% of discordant cases.Conclusions: The high rate of discordant results between Xpert and MTBDRplus has important implications for the laboratory, clinician and patient. While root causes for discordant result are multiple, a follow-up Xpert assay could guide healthcare workers to the correct treatment in most patients. [ABSTRACT FROM AUTHOR]

Published
2020
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28. Drug-Penetration Gradients Associated with Acquired Drug Resistance in Patients with Tuberculosis

Author

Dheda, Keertan, primary, Lenders, Laura, additional, Magombedze, Gesham, additional, Srivastava, Shashikant, additional, Raj, Prithvi, additional, Arning, Erland, additional, Ashcraft, Paula, additional, Bottiglieri, Teodoro, additional, Wainwright, Helen, additional, Pennel, Timothy, additional, Linegar, Anthony, additional, Moodley, Loven, additional, Pooran, Anil, additional, Pasipanodya, Jotam G., additional, Sirgel, Frederick A., additional, van Helden, Paul D., additional, Wakeland, Edward, additional, Warren, Robin M., additional, and Gumbo, Tawanda, additional

Published
2018
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30. gyrA mutations and phenotypic susceptibility levels to ofloxacin and moxifloxacin in clinical isolates of Mycobacterium tuberculosis

Author

Sirgel, Frederick A., Warren, Robin M., Streicher, Elizabeth M., Victor, Thomas C., van Helden, Paul D., Böttger, Erik C., Sirgel, Frederick A., Warren, Robin M., Streicher, Elizabeth M., Victor, Thomas C., van Helden, Paul D., and Böttger, Erik C.

Abstract

Objectives To compare mutations in the quinolone resistance-determining region of the gyrA gene and flanking sequences with the MICs of ofloxacin and moxifloxacin for Mycobacterium tuberculosis. Methods The presence of mutations in 177 drug-resistant M. tuberculosis isolates was determined by DNA sequencing and the MICs quantified by MGIT 960. Results Single nucleotide polymorphisms were detected at codons 94 (n = 30), 90 (n = 12), 91 (n = 3), 89 (n = 1), 88 (n = 1) and 80 (n = 1). Four isolates with double mutations D94G plus A90V (n = 2) and D94G plus D94N (n = 2) reflect mixed populations. Agreement between genotypic and phenotypic susceptibility was high (≥97%) for both drugs. Mutant isolates had an MIC50 of 8.0 mg/L and an MIC90 of >10 mg/L for ofloxacin compared with an MIC50 and MIC90 of 2.0 mg/L for moxifloxacin. Codons 94 and 88 were linked to higher levels of fluoroquinolone resistance compared with codons 90, 91 and 89. The MIC distributions for the wild-type isolates ranged from ≤0.5 to 2.0 mg/L for ofloxacin and from ≤0.125 to 0.25 mg/L for moxifloxacin. However, 96% of the isolates with genetic alterations had MICs ≤2.0 mg/L for moxifloxacin, which is within its achievable serum levels. Conclusions This study provides quantitative evidence that the addition of moxifloxacin to extensively drug-resistant tuberculosis (XDR-TB) regimens based on a clinical breakpoint of 2.0 mg/L has merit. The use of moxifloxacin in the treatment of multidrug-resistant tuberculosis may prevent the acquisition of additional mutations and development of XDR-TB

Published
2017

31. Novel Antitubercular 6-Dialkylaminopyrimidine Carboxamides from Phenotypic Whole-Cell High Throughput Screening of a SoftFocus Library: Structure–Activity Relationship and Target Identification Studies

Author

Wilson, Colin R., Gessner, Richard K., Moosa, Atica, Seldon, Ronnett, Warner, Digby F., Mizrahi, Valerie, Soares de Melo, Candice, Simelane, Sandile B., Nchinda, Aloysius, Abay, Efrem, Taylor, Dale, Njoroge, Mathew, Brunschwig, Christel, Lawrence, Nina, Boshoff, Helena I. M., Barry, Clifton E., Sirgel, Frederick A., van Helden, Paul, Harris, C. John, Gordon, Richard, Ghidelli-Disse, Sonja, Pflaumer, Hannah, Boesche, Markus, Drewes, Gerard, Sanz, Olalla, Santos, Gracia, Rebollo-Lopez, Maria José, Urones, Beatriz, Selenski, Carolyn, Lafuente-Monasterio, Maria Jose, Axtman, Matthew, Lelièvre, Joël, Ballell, Lluis, Mueller, Rudolf, Street, Leslie J., Ghorpade, Sandeep R., and Chibale, Kelly

Abstract

A BioFocus DPI SoftFocus library of ∼35 000 compounds was screened against Mycobacterium tuberculosis(Mtb) in order to identify novel hits with antitubercular activity. The hits were evaluated in biology triage assays to exclude compounds suggested to function via frequently encountered promiscuous mechanisms of action including inhibition of the QcrB subunit of the cytochrome bc1complex, disruption of cell–wall homeostasis, and DNA damage. Among the hits that passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series was prioritized for hit to lead optimization. Compounds from this series were active against clinical Mtb strains, while no cross-resistance to conventional antituberculosis drugs was observed. This suggested a novel mechanism of action, which was confirmed by chemoproteomic analysis leading to the identification of BCG_3193 and BCG_3827 as putative targets of the series with unknown function. Initial structure–activity relationship studies have resulted in compounds with moderate to potent antitubercular activity and improved physicochemical properties.

Published
2024
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32. embB 306 Mutations as Molecular Indicators to Predict Ethambutol Susceptibility in Mycobacterium tuberculosis

Author

Sirgel, Frederick A, Warren, Robin M, Streicher, Elizabeth M, Victor, Thomas C, van Helden, Paul D, Böttger, Erik C, University of Zurich, and Sirgel, Frederick A

Subjects
3004 Pharmacology, 10179 Institute of Medical Microbiology, 3002 Drug Discovery, 570 Life sciences, biology, 2736 Pharmacology (medical), 610 Medicine & health, 2730 Oncology, 2725 Infectious Diseases
Published
2012

33. Pyrrolo[3,4-c]pyridine-1,3(2H)-diones: A Novel Antimycobacterial Class Targeting Mycobacterial Respiration

Author

van der Westhuyzen, Renier, primary, Winks, Susan, additional, Wilson, Colin R., additional, Boyle, Grant A., additional, Gessner, Richard K., additional, Soares de Melo, Candice, additional, Taylor, Dale, additional, de Kock, Carmen, additional, Njoroge, Mathew, additional, Brunschwig, Christel, additional, Lawrence, Nina, additional, Rao, Srinivasa P.S., additional, Sirgel, Frederick, additional, van Helden, Paul, additional, Seldon, Ronnett, additional, Moosa, Atica, additional, Warner, Digby F., additional, Arista, Luca, additional, Manjunatha, Ujjini H., additional, Smith, Paul W., additional, Street, Leslie J., additional, and Chibale, Kelly, additional

Published
2015
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36. NovelkatGmutations causing isoniazid resistance in clinicalM. tuberculosisisolates

Author

Torres, Jessica N, primary, Paul, Lynthia V, additional, Rodwell, Timothy C, additional, Victor, Thomas C, additional, Amallraja, Anu M, additional, Elghraoui, Afif, additional, Goodmanson, Amy P, additional, Ramirez-Busby, Sarah M, additional, Chawla, Ashu, additional, Zadorozhny, Victoria, additional, Streicher, Elizabeth M, additional, Sirgel, Frederick A, additional, Catanzaro, Donald, additional, Rodrigues, Camilla, additional, Gler, Maria Tarcela, additional, Crudu, Valeru, additional, Catanzaro, Antonino, additional, and Valafar, Faramarz, additional

Published
2015
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37. Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients

Author

Zvada, Simbarashe P., Denti, Paolo, Sirgel, Frederick A., Chigutsa, Emmanuel, Hatherill, Mark, Charalambous, Salome, Mungofa, Stanley, Wiesner, Lubbe, Simonsson, Ulrika S. H., Jindani, Amina, Harrison, Thomas, McIlleron, Helen M., Zvada, Simbarashe P., Denti, Paolo, Sirgel, Frederick A., Chigutsa, Emmanuel, Hatherill, Mark, Charalambous, Salome, Mungofa, Stanley, Wiesner, Lubbe, Simonsson, Ulrika S. H., Jindani, Amina, Harrison, Thomas, and McIlleron, Helen M.

Abstract

Pharmacokinetic exposure and the MIC of fluoroquinolones are important determinants of their efficacy against Mycobacterium tuberculosis. Population modeling was used to describe the steady-state plasma pharmacokinetics of moxifloxacin in 241 tuberculosis (TB) patients in southern Africa. Monte Carlo simulations were applied to obtain the area under the unbound concentration-time curve from 0 to 24 h (fAUC(0-24)) after daily doses of 400 mg or 800 mg moxifloxacin and 800 mg ofloxacin. The MIC distributions of ofloxacin and moxifloxacin were determined for 197 drug-resistant clinical isolates of Mycobacterium tuberculosis. For a specific MIC, the probability of target attainment (PTA) was determined for target fAUC(0-24)/MIC ratios of >= 53 and >= 100. The PTAs were combined with the MIC distributions to calculate the cumulative fraction of response (CFR) for multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Even with the less stringent target ratio of >= 53, moxifloxacin at 400 mg and ofloxacin at 800 mg achieved CFRs of only 84% and 58% for multidrug-resistant isolates with resistance to an injectable drug, while the 800-mg moxifloxacin dose achieved a CFR of 98%. Using a target ratio of >= 100 for multidrug-resistant strains (without resistance to injectable agents or fluoroquinolones), the CFR was 88% for moxifloxacin and only 43% for ofloxacin, and the higher dose of 800 mg moxifloxacin was needed to achieve a CFR target of >90%. Our results indicate that moxifloxacin is more efficacious than ofloxacin in the treatment of MDR-TB. Further studies should determine the optimal pharmacodynamic target for moxifloxacin in a multidrug regimen and clarify safety issues when it is administered at higher doses.

Published
2014
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39. Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients

Author

Zvada, Simbarashe P., primary, Denti, Paolo, additional, Sirgel, Frederick A., additional, Chigutsa, Emmanuel, additional, Hatherill, Mark, additional, Charalambous, Salome, additional, Mungofa, Stanley, additional, Wiesner, Lubbe, additional, Simonsson, Ulrika S. H., additional, Jindani, Amina, additional, Harrison, Thomas, additional, and McIlleron, Helen M., additional

Published
2014
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40. The rationale for using rifabutin in the treatment of MDR and XDR tuberculosis outbreaks

Author

Sirgel, Frederick A, Warren, Robin M, Böttger, Erik C, Klopper, Marisa, Victor, Thomas C, van Helden, Paul D, Sirgel, Frederick A, Warren, Robin M, Böttger, Erik C, Klopper, Marisa, Victor, Thomas C, and van Helden, Paul D

Abstract

Genetically related Mycobacterium tuberculosis strains with alterations at codon 516 in the rpoB gene were observed amongst a substantial number of patients with drug resistant tuberculosis in the Eastern Cape Province (ECP) of South Africa. Mutations at codon 516 are usually associated with lower level rifampicin (RIF) resistance, while susceptibility to rifabutin (RFB) remains intact. This study was conducted to assess the rationale for using RFB as a substitution for RIF in the treatment of MDR and XDR tuberculosis outbreaks. Minimum inhibitory concentrations (MICs) of 34 drug resistant clinical isolates of M tuberculosis were determined by MGIT 960 and correlated with rpoB mutations. RFB MICs ranged from 0.125 to 0.25 µg/ml in the 34 test isolates thereby confirming phenotypic susceptibility as per critical concentration (CC) of 0.5 µg/ml. The corresponding RIF MICs ranged between 5 and 15 µg/ml, which is well above the CC of 1.0 µg/ml. Molecular-based drug susceptibility testing provides important pharmacogenetic insight by demonstrating a direct correlation between defined rpoB mutation and the level of RFB susceptibility. We suggest that isolates with marginally reduced susceptibility as compared to the epidemiological cut-off for wild-type strains (0.064 µg/ml), but lower than the current CC (≤0.5 µg/ml), are categorised as intermediate. Two breakpoints (0.064 µg/ml and 0.5 µg/ml) are recommended to distinguish between susceptible, intermediate and RFB resistant strains. This concept may assist clinicians and policy makers to make objective therapeutic decisions, especially in situations where therapeutic options are limited. The use of RFB in the ECP may improve therapeutic success and consequently minimise the risk of ongoing transmission of drug resistant M. tuberculosis strains.

Published
2013

41. gyrA mutations and phenotypic susceptibility levels to ofloxacin and moxifloxacin in clinical isolates of Mycobacterium tuberculosis

Author

Sirgel, Frederick A, Warren, Robin M, Streicher, Elizabeth M, Victor, Thomas C, van Helden, Paul D, Böttger, Erik C, Sirgel, Frederick A, Warren, Robin M, Streicher, Elizabeth M, Victor, Thomas C, van Helden, Paul D, and Böttger, Erik C

Abstract

OBJECTIVES: To compare mutations in the quinolone resistance-determining region of the gyrA gene and flanking sequences with the MICs of ofloxacin and moxifloxacin for Mycobacterium tuberculosis. METHODS: The presence of mutations in 177 drug-resistant M. tuberculosis isolates was determined by DNA sequencing and the MICs quantified by MGIT 960. RESULTS: Single nucleotide polymorphisms were detected at codons 94 (n = 30), 90 (n = 12), 91 (n = 3), 89 (n = 1), 88 (n = 1) and 80 (n = 1). Four isolates with double mutations D94G plus A90V (n = 2) and D94G plus D94N (n = 2) reflect mixed populations. Agreement between genotypic and phenotypic susceptibility was high (≥97%) for both drugs. Mutant isolates had an MIC(50) of 8.0 mg/L and an MIC(90) of >10 mg/L for ofloxacin compared with an MIC(50) and MIC(90) of 2.0 mg/L for moxifloxacin. Codons 94 and 88 were linked to higher levels of fluoroquinolone resistance compared with codons 90, 91 and 89. The MIC distributions for the wild-type isolates ranged from ≤0.5 to 2.0 mg/L for ofloxacin and from ≤0.125 to 0.25 mg/L for moxifloxacin. However, 96% of the isolates with genetic alterations had MICs ≤2.0 mg/L for moxifloxacin, which is within its achievable serum levels. CONCLUSIONS: This study provides quantitative evidence that the addition of moxifloxacin to extensively drug-resistant tuberculosis (XDR-TB) regimens based on a clinical breakpoint of 2.0 mg/L has merit. The use of moxifloxacin in the treatment of multidrug-resistant tuberculosis may prevent the acquisition of additional mutations and development of XDR-TB.

Published
2012

43. Emergence and treatment of multidrug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in South Africa

Author

Streicher, Elizabeth M., primary, Müller, Borna, additional, Chihota, Violet, additional, Mlambo, Charmaine, additional, Tait, Marisa, additional, Pillay, Manormoney, additional, Trollip, Andre, additional, Hoek, Kim G.P., additional, Sirgel, Frederick A., additional, Gey van Pittius, Nicolaas C., additional, van Helden, Paul D., additional, Victor, Thomas C., additional, and Warren, Robin M., additional

Published
2012
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44. Mutations in therrsA1401G Gene and Phenotypic Resistance to Amikacin and Capreomycin inMycobacterium tuberculosis

Author

Sirgel, Frederick A., primary, Tait, Marisa, additional, Warren, Robin M., additional, Streicher, Elizabeth M., additional, Böttger, Erik C., additional, van Helden, Paul D., additional, Gey van Pittius, Nicolaas C., additional, Coetzee, Gerrit, additional, Hoosain, Ebrahim Y., additional, Chabula-Nxiweni, Mamisa, additional, Hayes, Cindy, additional, Victor, Thomas C., additional, and Trollip, André, additional

Published
2012
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48. embB306 Mutations as Molecular Indicators to Predict Ethambutol Susceptibility in Mycobacterium tuberculosis.

Author

Sirgel, Frederick A., Warren, Robin M., Streicher, Elizabeth M., Victor, Thomas C., van Helden, Paul D., and Böttger, Erik C.

Subjects
*GENETIC mutation, *LOGICAL prediction, *ETHAMBUTOL, *MYCOBACTERIUM tuberculosis, *MICROBIAL sensitivity tests, *CLINICAL trials, *DRUG resistance in bacteria, *MICROBIAL mutation
Abstract

Background: Discordant results in conventional susceptibility testing of ethambutol against Mycobacterium tuberculosis may lead to underreporting of drug resistance. Methods: A 240-bp region of the embB gene in 111 clinical isolates of M. tuberculosis was sequenced and examined for mutations linked to ethambutol resistance. The phenotypic susceptibility levels of the isolates were quantified by the BACTEC™ MGIT 960™ TB System and correlated with the genotypic test results. These data were analyzed to find information that could be used to clarify discordant ethambutol susceptibility test results. Results: Mutations M306I (n = 56), M306V (n = 18) and M306L (n = 3) in M. tuberculosis showed decreased susceptibility to ethambutol. The minimum inhibitory concentrations (MICs) in 73% (56/77) of embB306 mutants were at or just above the critical concentration (MICs, 5.0 to ≤12.5 μg/ml) of ethambutol reflecting borderline (or intermediate) resistance. Eight ethambutol-resistant isolates lacked embB mutations, probably due to mutational alterations elsewhere in the genome. Conclusion: Our findings suggest that clinical isolates containing embB306 mutations with MICs overlapping the critical concentration are associated with discordant ethambutol susceptibility test results. The clinical significance of borderline resistance in combination treatment of tuberculosis remains to be determined before alternative ethambutol breakpoints are considered. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Published
2013
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50. Early Bactericidal Activity of Amoxicillin in Combination with Clavulanic Acid in Patients with Sputum Smear-positive Pulmonary Tuberculosis.

Author

Donald, Peter R., Sirgel, Frederick A., Venter, Amor, Parkin, Donald P., Van De Wal, Bernard W., Barendse, Asa, Smit, Elizabeth, Carman, David, Talent, Jennifer, and Maritz, Johannes

Subjects
*ANTITUBERCULAR agents, *TUBERCULOSIS treatment, *AMOXICILLIN, *CLAVULANIC acid, *DRUG efficacy
Abstract

The early bactericidal activity (EBA) of an antituberculosis agent is the rate of decrease in viable colony-forming units (CFU) per milliliter of sputum during the first 2 d of treatment of patients with previously untreated smear-positive pulmonary tuberculosis. The objective of this open randomized study was to evaluate the EBA of the combination of amoxicillin 3 g and clavulanic acid 750 mg. Ten patients with a mean age of 34 y and a mean weight of 56 kg received amoxicillin/clavulanic acid and 5 patients with a mean age of 34 y and a mean weight of 57 kg received no drug. In the patients receiving 1 dose of amoxicillin/clavulanic acid daily for 2 d the mean log[sub 10]CFU/ml of sputum before treatment was 6.7402 (SD 0.539) and after 2 d of treatment 6.7046 (SD 0.609); the corresponding values in patients receiving no drug were 6.7823 (SD 0.563) and 6.7502 (SD 0.673), respectively. The EBA of 0.018 (SD 0.130) in patients receiving amoxicillin/clavulanic acid did not differ significantly from that of 0.016 (SD 0.069) in patients receiving no drug. It is unlikely that the combination of amoxicillin/clavulanic acid has an important place in the treatment of tuberculosis with the exception of those patients with multidrug-resistant tuberculosis who are otherwise therapeutically destitute. [ABSTRACT FROM AUTHOR]

Published
2001
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